1. Field of the Invention
This invention relates to the field of aqueous enteric film coating of pharmaceutical tablets and the like for preventing release of the ingredients of the coated tablet in the gastric juices of the stomach and for releasing the ingredients of the tablet in the intestines, and more particularly concerns providing a fully-formulated, non-toxic, edible, enteric, film-coating, dry powder composition based on an acrylic resin for use in making an aqueous enteric coating suspension that may be used in coating pharmaceuticals with an intestinally soluble coating that is insoluble in gastric juices of the stomach.
2. Description of the Prior Art
Several aqueous enteric film-coating systems are known. These include the AQUATERIC system, based on cellulose acetate phthalate, the SURETERIC system, based on polyvinylacetate phthalate (PVAP), and the EUDRAGIT L system, based on copolymers of acrylic acid esters and methacrylic acid. Both the AQUATERIC and EUDRAGIT L systems require at least three processing steps to form the enteric coating suspension. With the AQUATERIC system, the AQUATERIC powder is dispersed in water followed by stepwise addition of plasticizer Tween 80 and optional pigments to form the AQUATERIC suspension. The EUDRAGIT L system is available as a powder (L100-55) or as an aqueous dispersion (L30-D). The xe2x80x9cEUDRAGIT L Technical Application Pamphlet (Info LD-13/e)xe2x80x9d published by Rohm Pharma GmbH specifies a step-wise procedure to prepare an aqueous enteric dispersion which includes: 1) addition of the EUDRAGIT L100-55 powder to water; 2) dropwise addition of a pre-calculated amount of aqueous sodium hydroxide solution; 3) stirring of the dispersion for 30 minutes using a simple stirrer running at a medium and controllable speed; 4) filtration of the suspension; 5) subsequent addition of an aqueous solution of plasticizer (at a recommended use level of 10% by weight with respect to the EUDRAGIT L100-55 powder), xe2x80x9cseparating agentxe2x80x9d, and anti-foam to the filtered suspension; 6) further stirring; and 7) final filtration. Special precautions noted in this pamphlet include the warning that coagulation of the EUDRAGIT L aqueous dispersion may occur as a result of the presence of electrolytes, foam formation, exposure to heat and frost, the presence of finely divided pigments and exposure to high shear gradients when using fast-running stirrers and mills. Special attention is also drawn to the requirement to observe the specified formulation ratios, as a deviation could result in the formation of coagulum, which as set out in the pamphlet is xe2x80x9cimpossiblexe2x80x9d to redisperse rendering the entire aqueous dispersion xe2x80x9cunusable.xe2x80x9d
The EUDRAGIT L30-D suspension is a dispersion of ethyl acrylate/methacrylic acid copolymer, 30% by weight in water. The xe2x80x9cEUDRAGIT L Technical Application Pamphlet (Info LD-11 /e)xe2x80x9d published by Rohm Pharma GmbH specifies a multi-step process for forming a complete aqueous dispersion system based on EUDRAGIT L30-D suspension that includes: 1) addition of plasticizer; 2) addition of a xe2x80x9cseparating agentxe2x80x9d; 3) addition of an anti-foam; 4) optional addition of pigments; 5)stirring; and 6) final filtration. Special precautions, identical to those described for EUDRAGIT L100-55 powder, are also indicated in the EUDRAGIT L30-D suspension pamphlet.
The SURETERIC composition, which is described in Colorcon U.S. Pat. No. 5,733,575, which is incorporated herein by reference, advanced the art in the field by teaching the complete formulation of an enteric film coating pre-mix, which may be dispersed readily in water along with an anti-foam in two steps. The SURETERIC system requires the addition of a viscosity modifier to prevent settling of the suspended solids in the resulting aqueous dispersion during coating.
Lehmann et al. U.S. Pat. No. 4,520,172, which is incorporated herein by reference, discloses a binary mixture of EUDRAGIT L copolymer and a suitable alkalizing agent or xe2x80x9csalt-forming agent.xe2x80x9d However, there are no known enteric film-coating systems based on the copolymer of ethyl acrylate and methyacrylic acid of the EUDRAGIT L system that are analogous to the SURETERIC system. Further, given the precautions cited in the Rohm Pharma literature and the chemical differences between PVAP and the methacrylic acid/ethyl acrylate copolymers, it would be surprising and unexpected if the Lehmann et al. binary system could be expanded into a fully-formulated solid composition which could then be dispersed readily in water for use in providing an enteric film coating.
It is an object of this invention to provide a fully-formulated, enteric film coating composition based on EUDRAGIT L copolymers that may be readily dispersed in water and applied to pharmaceutical tablets and the like.
Another object of this invention is to provide a fully formulated, enteric film coating composition based on EUDRAGIT L copolymers which does not cake upon preparation.
Another object of this invention is to provide a fully formulated, enteric film coating composition based on EUDRAGIT L copolymers which does not form agglomerates upon storage at elevated temperature and humidity.
Another object of this invention is to provide a fully-formulated, enteric film coating composition based on EUDRAGIT L copolymers which may be dispersed readily into water to form a coating dispersion that when applied to pharmaceutical tablets produces a tack-free coating.
Another object of this invention is to provide a fully formulated, enteric film coating composition, containing lake pigment and neutralizing agent, said lake pigment being stable upon dispersion in water.
Another object of this invention is to provide a fully-formulated, enteric film coating composition based on EUDRAGIT L copolymers which may be dispersed readily into water to form a coating dispersion that when applied to pharmaceutical tablets produces a film coating having an exceptional degree of film strength. This exceptional film strength is manifested by excellent performance in a xe2x80x9cstressed disintegration test.xe2x80x9d
Another object of this invention is to provide a fully formulated, enteric film coating composition based on EUDRAGIT L copolymers that disperses in water without the formation of coagulum.
Another object of this invention is to reduce the number of steps in the preparation of aqueous film coating dispersions based on EUDRAGIT L copolymers from six (6) or more to two (2), thereby achieving the beneficial result of reducing the overall preparation time for preparing aqueous film coating dispersions from about 90 minutes to about 20 minutes.
These and other objects of the invention are accomplished by our invention, which is described below.
In accordance with the invention, our non-toxic, edible, enteric film coating, dry powder composition for use in making an aqueous enteric suspension which may be used in coating pharmaceutical tablets comprises an acrylic resin (e.g., EUDRAGIT L copolymers), an alkalizing agent, and a detackifier. Optionally but advantageously, our dry powder composition may also include one or more of the following additives: a plasticizer; a pigment; a flow aid; a surfactant; an anti-agglomerating agent; a secondary film former; and a secondary detackifier. In a particularly preferred embodiment of this invention, the inventive dry powder composition contains an acrylic resin, an alkalizing agent, a detackifier, a plasticizer, a pigment, a flow aid, a surfactant, an anti-agglomerating agent, a secondary film-former and a secondary detackifier.
A method of making the inventive dry powder composition comprises the steps of mixing an acrylic resin with an alkalizing agent, detackifier, and optionally with one or more of the following additives: a plasticizer; a pigment; a flow aid; a surfactant; an anti-agglomerating agent; a secondary film former; and a secondary detackifier. The resulting enteric film coating dry powder composition and a separately-added anti-foam is readily dispersed in water, preferably deionized water, using a high shear mixer and is ready to use in 15-30 minutes. A high shear mixer is used rather than a slower stirrer to eliminate the formation of coagulum.
In accordance with the invention, a method of coating substrates, such as pharmaceutical tablets and the like, comprises mixing sequentially anti-foam and the inventive dry composition into water to form a coating suspension, applying the coating suspension onto the substrate to be coated to form a film coating on the substrates, and drying the film coating on the substrates.
The enteric polymer is an acrylic resin which comprises at least one vinyl or vinylidene moiety having a carboxylic acid group capable of salt formation. The acrylic resin may comprise of at least one vinyl or vinylidene moiety having a carboxylic acid group capable of salt formation and at least one alkyl acrylate or alkyl methacrylate moiety. The acrylic resin also may comprise of at least one vinyl or vinylidene moiety having a carboxylic acid group capable of salt formation, at least one alkyl acrylate or alkyl methacrylate moiety, and at least one other vinyl or vinylidene moiety copolymerizable with a) the alkyl acrylate or alkyl methacrylate moiety and b) the vinyl or vinylidene moiety having a carboxylic acid group capable of salt formation. Further, the acrylic resin may comprise of at least one vinyl or vinylidene moiety having a carboxylic acid group capable of salt formation and at least one other vinyl or vinylidene moiety copolymerizable with the vinyl or vinylidene moiety having a carboxylic acid group capable of salt formation.
Preferably, the enteric polymer is an acrylic resin which is comprised of: (1) from 20 to 85 percent by weight of at least one alkyl acrylate or alkyl methacrylate moiety; (2) from 80 to 15 percent by weight of at least one vinyl or vinylidene moiety having a carboxylic acid group capable of salt formation; and (3) from 0 to 30 percent by weight of at least one other vinyl or vinylidene moiety copolymerizable with (1) and (2). In a particularly preferred embodiment of this invention, the alkyl acrylate (1) is ethyl acrylate, and the vinyl moiety (2) is methacrylic acid. EUDRAGIT L100-55 powder is one example of a copolymer system meeting this definition.
Preferably, the acrylic resin comprises about 20% to about 80% by weight of the dry coating composition of the invention.
The alkalizing agent may be a bicarbonate, a carbonate, a phosphate, or a hydroxide of sodium or potassium, magnesium carbonate, magnesium hydroxide, ammonium carbonate, ammonium bicarbonate, magnesium oxide, calcium hydroxide, or mixtures thereof. The quantity of alkalizing agent used is directly dependent on the amount of carboxylic acid-bearing vinyl or vinylidene moiety present in the acrylic resin. Specifically, said alkalizing agent is added in a quantity such that, after reaction with the acrylic resin, 0.1 to 10 mole percent of the acidic groups are present in the salt form.
The detackifier may be talc, aluminum hydrate, glyceryl monostearate, kaolin, or mixtures thereof and is used principally to reduce the incidence of tablet-to-tablet sticking that can occur during the film coating of pharmaceutical tablets and the like using aqueous dispersions based on the inventive compositions. Preferably, the detackifier comprises about 5% to about 40% by weight of the dry coating composition of the invention.
The plasticizer may be triethylcitrate, glyceryltriacetate, acetyltriethylcitrate, dibutyl sebacate, diethylphthalate, polyethylene glycol having a molecular weight in the range of 200 to 8000, glycerol, castor oil, copolymers of propylene oxide and ethylene oxide, or mixtures thereof. When no plasticizer is included in the dry powder composition of the invention, the plasticizer is mixed separately into the coating suspension of the invention. Preferably, the plasticizer comprises 0% to about 20% by weight of the coating composition of the invention, and more preferably, the plasticizer comprises about 2% to about 20% by weight of the dry coating composition of the invention.
The pigment may be an FDandC or a DandC lake, titanium dioxide, magnesium carbonate, talc, pyrogenic silica, iron oxides, channel black, riboflavin, carmine 40, curcumin, annatto, insoluble dyes, pearlescent pigments based on mica and/or titanium dioxide or mixtures thereof. Other examples of suitable pigments are listed in Jeffries U.S. Pat. No. 3,149,040; Butler, et. al. U.S. Pat. No. 3,297,535; and Colorcon U.S. Pat. No. 3,981,984; all of which are incorporated herein by reference. The pigment may also include lake blends which contain a plasticizer and OPADRY pigmented coating compositions, some of which are disclosed in Colorcon U.S. Pat. No. 4,543,370 , which is incorporated herein by reference. Preferably, the pigment comprises 0% to about 50% by weight of the inventive dry coating composition.
The flow aid may be silica such as fumed silica, supplied under the tradename Cab-O-Sil by Cabot, Inc. The flow aid imparts flowability to the powdered composition during dry blending and subsequent transferring from the blender to a storage container. Preferably, the flow aid comprises 0% to about 3% by weight of the inventive dry coating composition.
The surfactant may be sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate 80, Tween 80, or mixtures thereof. Preferably, the surfactant comprises 0% to about 5% by weight of the inventive dry composition.
The anti-agglomerating agent may be kaolin. The quantity of anti-agglomerating agent in the inventive dry coating composition ranges from 0% to about 40% by weight of the inventive dry coating composition. Surprisingly, it has been found that relatively low levels of kaolin prevent clumping during preparation of the powdered composition and during storage of the final composition at elevated temperature and humidity. Preferably, kaolin is used at levels from greater than 0 percent to about 40% by weight of the composition. It has unexpectedly been found that a given level of kaolin imparts a much greater level of anti-agglomerating effect than the same amount of talc or silica, which are also known to be anti-agglomerating agents. Beneficially, kaolin serves both as an anti-agglomerating agent and a detackifier.
The secondary film former may be xanthan gum, sodium alginate, propylene glycol alginate, hydroxypropylmethylcellulose (HPMC), hydroxyethylecellulose (HEC), sodium carboxymethylcellulose (sodium CMC), polyvinylpyrrolidone (PVP), Konjac flour, carrageenan, other film-forming polymer or mixtures thereof. Preferably, the amount of secondary film former in the coating composition ranges from 0% to about 5% by weight of the dry coating composition of the invention. Use of the secondary film former improves the film strength of the inventive composition. Surprisingly, very low levels of a secondary film former can improve film strength as demonstrated by coating performance in the xe2x80x9cstressed enteric testxe2x80x9d developed by Colorcon. In a preferred embodiment of this invention, the incorporation of xanthan gum at a level of 0.5% by weight of the inventive composition resulted in superior stressed enteric test results when compared to a composition without xanthan gum.
The second detackifier may be sodium sulfate, calcium sulfate, calcium chloride, other inorganic or organic water-sequestering agents or mixtures thereof. Preferably, the amount of secondary detackifier in the coating composition ranges from 0% to about 5% by weight of the inventive dry coating composition of the invention. Surprisingly, incorporation of very low levels (greater than 0 to 5% by weight) of secondary detackifier results in a dramatic reduction of tablet tackiness, after being film-coated using the inventive aqueous dispersions in the most tackprone formulations. In a preferred embodiment of this invention, incorporation of calcium sulfate, at a level of only 0.15% by weight of the composition, results in the formation of tack-free tablets when coated with the inventive aqueous dispersions. Surprisingly, a given level of calcium sulfate or similar water-sequestering compound is much more effective in reducing coated tablet tack than identical levels of other known detackifiers such as talc and glyceryl monostearate. It is postulated that the secondary detackifier is functioning as a water-sequestering agent and binds free water on the tablet surface, preventing interaction of the water with the coalescing polymer, thereby effectively increasing the polymer glass transition temperature (Tg) and its resistance to further softening and attendant sticking to like tablets.
It is particularly advantageous to incorporate as many of the benefit-imparting additives of the inventive compositions into one formulation as possible. Therefore, a particularly preferred embodiment of this invention is the composition comprising: 1) an acrylic resin, preferably about 20 to about 80% by weight of the composition; 2) an alkalizing agent, present in an amount such that between about 0.1 to 10 mole % of the carboxylic acid groups on the acrylic resin will be neutralized; 3) a detackifier, preferably in the range of about 5% to about 40% by weight of the composition; 4) a plasticizer, preferably in the range of about 2% to about 20% by weight of the composition; 5) a pigment, preferably in the range of greater than 0% to about 50% by weight of the composition; 6) a flow aid, preferably in the range of greater than 0% to about 3% by weight of the composition; 7) a surfactant, preferably in the range of greater than 0% to about 5% by weight of the composition; 8) an anti-agglomerating agent, preferably in the range of greater than 0% to 40% by weight of the composition; 9) a secondary film former, preferably in the amount of greater than 0% to about 5% by weight of the composition; and 10) a secondary detackifier, preferably in the amount of greater than 0% to about 5% by weight of the composition.
It has been unexpectedly found that when said fully-formulated composition, containing lake pigments, is dispersed in water, the lake pigment is completely stable. That is no color bleeding is observed. This is particularly surprising in light of current industry art which dictates that colorants be added to the dispersion only after the neutralization step (acrylic polymer reacted with neutralizing agent) is complete in order to avoid xe2x80x9ccolor bleeding.xe2x80x9d
A preferred method of preparing the inventive compositions is by conventional dry-blending using a xe2x80x9cV-blenderxe2x80x9d, food processor or similar device. Inventive compositions prepared by these conventional blending technologies are dispersed in aqueous solution prior to film-coating substrates, such as pharmaceutical tablets and the like, with the aid of a high shear mixer. Use of a high shear mixer allows the formation of a homogeneous aqueous dispersion without the formation of problematic coagulum. The following examples further illustrate the invention.